Contraceptive means

ABSTRACT

A cap device is coated externally and internally with a vaginal mucous membrane antiseptic and is formed of a water-soluble starch.

United States Patent [191 Forti et al.

[451 Oct. 9, 1973 CONTRACEPTIVE MEANS Inventors: Emilio Fol-ti, Rome; Carlo Del Guercio, Pisa; Giovanni Gazzani, Como, all of Italy Filed: Apr. 19, 1972 Appl. No.: 245,516

Related US. Application Data Continuation-impart of Ser. No. 878,232, Nov. 19, 1969, abandoned.

Foreign Application Priority Data Dec. 16, 1968 Italy 25160 A/68 U.S. Cl 128/271, 128/260, 424/16,

424/28, 424/35, 424/361 Int. Cl. A611 15/00 Field of Search 128/260, 271;

References Cited UNITED STATES PATENTS lshihama ct al 128/271 Jacqhignon Forti et al Lang et al...... Bice et a] Elias 424/307 Primary Examiner--Shep K. Rose Attorney-Robert D. Flynn et al.

ABSTRACT Acap device is coated externally and internally with a vaginal mucous membrane antiseptic and is formed of a water-soluble starch.

2 Claims, 2 Drawing Figures CONTRACEPTIVE MEANS RELATED APPLICATION This application is a continuation-in-part of application Ser. No. 878,232, filed Nov. 19, 1969 now abandoned.

The present invention relates to means applicable by male or female and having a mechanical, antiseptic and orthogenetic protective and preventive action, and to a method of producing such means.

As is generally known, the prevention of infection with diseases in sexual intercourse and also the necessity of a sufficient protection for eugenic reasons represent actual problems. Various means are already known which provide the effects referred to by mechanical or chemical means. Such means or agents comprise for example tablets, globules, pessaries, diaphragms, little sponges, tampons, creams and the like, which must be introduced into the vagina and which thus shift the severe responsibility for hygenics and also for the prevention of conception entirely to the female. Thisfact often causes psychic difficulties to the sensitiveness of female emotions; in addition, often the aid of a third person must be asked, e.g. in case of introducing pessaries or diaphragms.

On the other hand, means applicable by the male are already known such as e.g. condoms which, however, being a foreign body, have the disadvantage of exerting an irritating and desensibilizing effect and of necessitating subsequent removal. In addition, therapeutic medicaments must also often be introduced into the vagina, against which necessity there exist again prejudices and psychic scruples.

in all birth-control methods, with the exception of abstention, a risk of varying degree is found either from the view point of efficacy or side effects.

Medical literature provides epidemiological data in respect of every contraceptive technique. Though frequently at variance with each other because of difierent statistical methods used, all conclude that none is free of failures or side-effects and that the efficacy of every contraceptive method depends largely on the social, psychological and cultural conditions of the individuals using 'them.

This accounts for the search for more innocuous and effective contraceptives, easy to apply, without interfering with sexual sensation, and acceptable from the economic point of view. A new contraceptive of the intra-vaginal type has now been developed for the purpose of achieving the ideal characteristics described above.

This pharmacological association of spermicidally and germicidally active substances is available in the form of caps, which can be introduced into the vagina either by the male by application to the glans penis, or by the female to the os uteri, prior to sexual intercourse.

In accordance with the present invention, there is FIG. 2 is a view of an enlarged section of the cap.

In the Figures, C is a cap the starch sheet C, of which contains external layer A on the outer surface thereof and internal layer B on the inner surface thereof.

The starch is a water-soluble starch such as described in L. Adam-Cachets Azymes et cachets medicamenteux Paris 1928. The starch dissolves rapidly at the normal temperature of the human body (37C.) and upon contact with the moist vaginal membrane. Approximately 40 percent of the starch of the cap dissolves in water at 37C. in about 5 minutes and about 100 percent so dissolves in about 10 minutes. For example, a cap can have a diameter of approximately 22-24 mm and a weight of about 40 mg.

External surface layer A comprises about l824 mg containing 90 percent of Tween 20 (a polyoxyethylene sorbitan monolaurate) and 10-20 percent of active medicinal substances.

internal surface layer B comprises about 160-200 mg containing 80-90 percent of a mixture of excipients and about 20-10 percent of active medicinal substances. The ex'cipient mixture contains water-soluble lanolin, talc and Tween 20, in relative weight ratios ranging from about :7024 to 80:60:4, respectively.

in both layers A and B, the active medicinal substances comprise mixtures of phenylmercuric nitrate, benzethonium chloride and methyl p-oxybenzoate, the relative weightratios being in the range of from 2:4:25 and to 325220, respectively.

The caps according to this invention are superior to prior caps. The combination of the active substances mentioned above assures optimal medicinal action, while the nature and the proportions of the excipients assure other important advantages.

in particular, external layer A containing Tween 20 assures three advantages:

a. to put a part of the active substances into immediate contact with mucous membranes;

b. to delay by some seconds the softening of the starch cap in order that it may more easily reach its destination;

c. to prevent the sheet from sticking immediately to mucous membrane of the vagina, as occurs with the common cachets.

lntemal layer B containing water-soluble lanolin, besides serving as a vehicle for the remaining active substances, also acts as a paste or adhesive, allowing the cap to adhere to the glans penis or the os uteri on which it is applied.

The caps stability under normal environmental conditions is optimal (after 2 months exposure to normal environment, no alterations were observed). At 60C., stability is still highly satisfactory. It is also good when exposed to a high degree of humidity.

The spermicidal activity of the caps has been shown on bulls and men's sperm. The latter test (Bakers test) showed that one-eighth of a cap is sufficient to immobilize 4 ml. of human sperm within 5 minutes.

The absence of any local irritant activity of the caps has been confirmed by instillation in the conjunctival sack of a rabbit or by introducing it in the skin of a rabbits ear.

Experiments have demonstrated the bacteriostatic and bactericidal activity of the caps on organisms including Spirocheta pallida, Streptococcus cureus, and S. pyogenes, S. Lactis, Enterococcus, Pseudomonas pyocyanea and Trichomonas vaginalis.

lntravaginal tolerance of the caps has been studied by introducing daily for 20 days a previously determined dose of the product in the vagina of 10 rabbits. No local reactions or irritation were observed macroscopically or microscopically. The tolerance of the caps was demonstrated in a preliminary trial in women by the daily introduction in the vagina of one cap for 20 consecutive days, as illustrated in EXAMPLE 3, below.

The following examples illustrate the invention.

EXAMPLE 1 On the external surface of caps consisting of starch sheet having a diameter of 24 mm (1 inch), a layer was applied having a weight of 20 mg consisting of a homogeneous mixture of the following compounds:

Tween 20 17 Active substances 3 Upon the internal surface of the same caps, a layer having a weight of 180 mg was applied consisting of a homogeneous mixture of the following components:

mg Water soluble lanolin 83.2 Talc 66.0 Tween 20 4.1 Active substances 26.3

The active substances, in both layers contain, in turn, a mixture having the following composition (in weight):

parts pleienylmercuric nitrate 2.15 nzethonium chloride 4.55 methyl p-oxybenzoate 23.00

Phenylmercuric nitrate and benzethonium chloride are known to have bacteriostatic and bactericidal activity. A combination of the two substances is known to be more effective than either alone in arresting the activity of Spirocheta pallida, and is useful for the prevention and local treatment of venereal infection of the female genital organs.

EXAMPLE 2 The following tests were conducted in order to indicate the dissolution time of the starch caps such as those illustrated in EXAMPLE 1.

In order that the dissolution time of the caps could be better ascertained, a dye (Water-soluble Blue Re. Pi. Co.) was incorporated in the excipients, which dye had an absorption peak at 637 my At determined intervals the dye concentration was read on a spectrophotometer. In each cap, mg. dye were incorporated. Seven beakers containing exactly 100 ml. water were placed on a thermostatic water bath at 37C. corresponding to body temperature. When the temperature had reached the equilibrium value, seven caps were added successively. The contact time with water was 1 3 5 7 9 and 11 minutes respectively, whereas for the 7th beaker, the complete dissolution of the dye was permitted. This latter test served as a comparison for establishing the percentage values. In order to facilitate a homogeneous dissolution of the dye, the water was stirred slightly during the test with a glass rod.

At the end of each of the above-predetermined periods, ml. of the respective solutions were taken and additioned with 0.01 ml. 20% NaOH in order to set the pH of the solution and, therefore, stabilize the specific absorption of the dye. After centrifugation, the extinction of each of the resulting solution was determined on a spectrophotometer.

The results are shown on the following page.

TABLE I.-RESULTS OBTAINED FROM FOUR TESTS [The figures represent the spectrophotometric absorption at 637 11111.]

After (minutes)-- Total solu- 5 7 9 11. tion Average 465 1,221 1,683 2,382 2, 696 3,050 3,115

Percentage values, percent 14. 9 39.06 54. 02 76. 4 83. 3 97. 8

EXA MPLE 3 Clinical test data were obtained with starch caps having the following characteristics:

diameter 20 mm external layer A Tween 20 l7 mg medicinal components 3 mg internal layer B water-soluble lanolin 96.3 mg talc 66 mg Tween 20 4.1 mg medicinal components 20 mg the medicinal components of layers A and B phenylmercuric nitrate 2.05 mg benzethonium chloride 4.25 mg methyl p-oxybenzoate 17 mg The rate of the dissolution of the caps at 37C. (body temperature) has been calculated. About 40 percent of a cap is dissolved after 3 minutes and about 100 percent after 11 minutes.

Trials in humans were carried out inorder to evaluate the contraceptive activity, side effects and degree of acceptability of the caps.

One hundred and five couples of volunteers known to be fecund, were interviewed prior to their participation in the trial. of these, 1 1 couples renounced either because they did not trust the method, they preferred another, the husband was against it. In two of the couples pregnancy occurred before the test started. Of the remaining 94 couples, 30 accepted to use cap exclusively by male application, 58 exclusively by female application, while six varied the mode of application.

These couples were interviewed at regular intervals according to an established questionnaire, thus making it possible to collect information concerning the methods acceptance or objections, the tolerance and side effects of the cap, and pregnancy. The answers collected during the course of the interviews concerning the acceptance of the method have been transformed into statistical data and those concerning the efficacy of the method have been calculated according to the method of Pearl (Human Biol. 4, 363, 1932), which expresses the pregnancy index for 100 years of exposure by the following formula:

R total number of conceptions by l200/sum of months of exposure This index is considered more reliable for the study of the efficacy of contraceptives than simple percentages of success or failure.

None of the 94 couples who used the cap have reported any side effects, and it was well tolerated. There was a total absence of unpleasant sensations (such as burning, unctuousness, disagreeable odor, excessive lubrification of the vagina, etc.).

Nine couples out of 105 refused to take part in the experiment. In comparison to other methods this represents an extremely low proportion of refusals (about 8 percent).

The acceptance was always excellent on the part of the 94 couples who used the product. All of them used the method for at least 2 months. 16 couples interrupted thereafter the use of the cap for the following reasons: couples because they preferred another method, four because they did not trust this one and two because the husband was against it. 1 1 other couples did not continue use of the cap during the entire period allotted for the trial. Their motivation was not related to the method as such, but was due to a change of residence or because pregnancy occurred, as summarized in TABLE II below.

TABLE II Efficacy of the cap Number of Mean time of ob- Mode of Use couples servation (in months) male 30 9 female 58 8.7 mixed 6 l 1.8 Total 94 9.03

Years of Number of Index of Mode of Use exposure pregnancies pregnancy male 23 3 l3 female 43 3 6.9 mixed 6 0 Total 71 6 8.4

As can be seen from TABLE ll, six pregnancies occurred in the 94 couples who used the cap. There seems to be a slight difference between exclusively male and exclusively female application.

It is inherent in the nature of a limited clinical trial that there are limits in the sampling, the period of observation, etc. lt, nevertheless, permits extrapolation of the trend of a phenomenon when a more extensive trial is conducted. As this cap, which is entirely new, has obtained a high index of acceptance without causing any known side effects, its contraceptive efficacy can be assessed by comparing the results of the trial with reported results obtained with other contraceptive means. This comparison is shown in TABLE III, below.

It is evident that the data are not statistically comparable for several reasons (different number of tests, different sites of application etc.). It is nevertheless possible to deduce from TABLE [II a trend in favor of the cap of this invention, as its pregnancy index is the lowe t, h os f v ra e- V This comparison does not comprise the pill, which is the most effective contraceptive. Numerous authors agree in stating that the pill is effective in practically 100 percent of cases. It should, however, be observed that against these advantages side effects of the pill are described in numerous publications. In addition to these undesirable side effects there are other harmful effects: recent publications indicate on the bases of statistical analysis that the increase in the use of the pill had led to an increase in venereal diseases. This information based on epidemiological studies carried out in the countries where the pill has been freely available for many years, is attributed to the fact that women feeling safe from the fear of pregnancy, pay less attention to venereal diseases, which do not cause in the female a particularly severe subjective symptomatology. ln contrast to the starch caps of this invention, gelatin and polyvinyl alcohol caps have been proposed earlier. Gelatin, however, is substantially inferior to starch in: being substantially less resistant to heat; tends to harden and becomes less soluble with time; substantially slower in going into solution; and, while dissolving in the vagina, it gives a sensation of being greasy or slippery and is substantially less desirable aesthetically. Similarly, polyvinyl alcohol has the following disadvantages, not shared with starch: not tolerated by sensitive persons, tends to form lumps which dissolve slowly; less resistant to external stress and less stable with time; less readily and less comfortably inserted into the vagina.

We claim:

1. In a contraceptive in the form of a shell-shaped cap device adapted to conform to the glans penis or the os uteri, and having elastic consistency and melting properties in the female vagina, said cap having applied on the external surface thereof an external layer (A) functioning to put active substances thereof into immediate contact with mucous membranes of the vagina, and said cap having applied on the interior surface thereof an internal layer (B) functioning to allow the cap to adhere to the glans penis or the os uteri to which it is applied and to carry the remaining active substances, the improvement which comprises said cap device being formed from a cachet-type sheet of starch, about 40 percent of which dissolves in water at 37C. in about 5 minutes, and about 100 percent of which so dissolves in about 10 minutes,

a coating defining said external layer (A) on said external surface comprising from about to about percent by weight of polyoxyethylene sorbitan monolaurate, and from about 20 to about 10 percent by weight of a vaginal mucous membrane medicament, coating defining said internal layer on said inner surface comprising from about 80 to about 90 percent by weight of water-soluble lanolin, talc and polyoxyethylene sorbitan monolaurate as an excipient and from about 20 to about 10 percent by weight of the said vaginal mucous membrane antiseptic medicament, 

2. A device of claim 1 wherein the excipient of said inner surface coating comprises a water-soluble lanolin, talc and polyethylene sorbitan monolaurate having a relative weight ratio of from about 90:70:4 to about 80:60:4. 